Böttcher, K;
Longato, L;
Marrone, G;
Mazza, G;
Ghemtio, L;
Hall, A;
Luong, TV;
... Rombouts, K; + view all
(2021)
AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro.
American Journal of Physiology
, 320
(4)
G543-G556.
10.1152/ajpgi.00262.2020.
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Abstract
Tumour stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known TP53 or CTNBB1 mutations on primary human HSC activation, proliferation and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hHSC proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms (AMPKα1/α2-/-) and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Datamining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 (PRKAA1) and AMPKα2 (PRKAA2) expression differed depending on the mutation (TP53 or CTNNB1), tumour grading and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumour-promoting interactions between hHSC and HCC.
| Type: | Article |
|---|---|
| Title: | AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1152/ajpgi.00262.2020 |
| Publisher version: | https://doi.org/10.1152/ajpgi.00262.2020 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | AMPK, Hepatic Stellate Cells, Hepatocellular carcinoma, TCGA / LICA-FR, tumour-stromal interactions |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10119577 |
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